The University of California at Los Angeles - Boston University Molecular Characterization Laboratory (UCLA- BU MCL) is a multidisciplinary, translational research program designed to enhance our understanding of the molecular, cellular and imaging features distinguishing indolent from aggressive lung cancers in screen- detected and non-screen-detected clinical settings. The National Lung Screening Trial (NLST) has provided compelling evidence of the efficacy of lung cancer screening using low-dose helical computed tomography (LDCT) to reduce lung cancer mortality. The benefits of screening, however, must be reconciled with its potential harms, including high false positive rates and the potential for overdiagnosis. Our broad goal is to distinguish indolent from aggressive lesions by interrogating the molecular, microenvironment and imaging features that are associated with clinical outcomes. This global approach brings all aspects of these investigations to bear on our understanding of the molecular pathogenesis of early stage lung cancer. These results will be translated to the clinical management of screen-detected lung cancer. Understanding the factors underlying tumor indolence or aggression that result in heterogeneous clinical outcomes will facilitate clinical decision making in the context of lung cancer screening, increase screening effectiveness and ultimately drive care pathways. We hypothesize that the pathways underlying heterogeneity in screen-detected lung cancers will be revealed by analysis of molecular (whole exome and mRNA sequencing), microenvironment (immune and inflammatory mediators) and imaging characteristics (semantic and quantitative features) of screen- detected lesions. The specific aims are: Aim 1: Identify molecular, cellular and imaging profiles that distinguish screen-detected from non-screen- detected lung cancers. Aim 2: Identify molecular, cellular and imaging profiles that distinguish screen-detected lung cancers with indolent versus aggressive clinical courses from the NLST. Aim 3: Confirm and refine molecular, cellular and imaging profiles that distinguish screen-detected lung cancers with indolent versus aggressive clinical courses from a prospectively collected screening cohort. Cases will derive from the NLST biorepository, DECAMP cohorts and a University of California (UC) state-wide initiative involving the five UC academic medical centers that are establishing a common screening policy and platform that involves the collection and archiving of clinical, imaging, and tissue specimens.